De NovoPyrimidine Biosynthesis Connects Cell Integrity to Amphotericin B Susceptibility in Cryptococcus neoformans

Abstract

Synergy between AmB and nucleotide biosynthetic pathways has been documented, but the mechanism of this interaction has not been delineated. Results from this study suggest a correlation between uridine nucleotide biosynthesis and cell integrity likely mediated through the pool of nucleotide-sugar conjugates, which are precursor molecules for both capsule and cell wall of C. neoformans. Thus, we propose a mechanism by which structural defects in the cell wall resulting from perturbation of pyrimidine biosynthesis allow faster and increased penetration of AmB molecules into the cell membrane. Overall, our work demonstrates that impairment of pyrimidine biosynthesis in C. neoformans could be a potential target for antifungal therapy, either alone or in combination with AmB.

The Aspergillus fumigatus Sialidase (Kdnase) Contributes to Cell Wall Integrity and Virulence in Amphotericin B-Treated Mice

“…Species or strains with high levels of chitin in their cell wall were shown to be more susceptible to challenge with amphotericin B ( Bahmed et al, 2003 ). In the yeast pathogen, Cryptococcus neoformans , Banerjee et al (2016) created a ura1 Δ mutant lacking dihydroorotate dehydrogenase that showed both compromised cell wall structure and increased susceptibility to AB. They proposed that decreased nucleotide-sugar pools in the mutant resulted in structural defects in the cell wall that in turn, allowed a more rapid entry and greater binding of AB to the plasma membrane.…”

Membrane Integrity Contributes to Resistance of Cryptococcus neoformans to the Cell Wall Inhibitor Caspofungin

“…However, deleting the Pkc1 kinase in the CWI pathway results in severe cell wall defects and a much lower MIC for caspofungin (unpublished observations; 9 ). Studies in the past few years have identified a beta-subunit of a lipid translocase, encoded by CDC50 ( CNAG_06465 ), and a dihydroorotate dehydrogenase (DHOH), encoded by URA1 ( CNAG_02794 ), that both play a role in resistance to caspofungin ( 8 , 10 ). More recently, the Cdc50 protein was proposed to interact with a calcium channel protein to regulate calcium homeostasis, whereas the DHOH enzyme is required for de novo pyrimidine synthesis ( 11 ).…”

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

“…In animal models of infection, pyrimidine biosynthesis mutants from several pathogenic fungi are highly attenuated for virulence, including A. fumigatus, [112] C. albicans [113], H. capsulatum [114], and C. neoformans. [115,116] Evidence in the literature thus appears to support the targeting of pyrimidine biosynthesis as a valid antifungal strategy. A library of 340,292 small molecules was screened in vitro against A. fumigatus, and multiple chemical series with antifungal activity were identified [33].…”